Carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical agents comprising the same as active ingredient

ABSTRACT

A carboxylic acid derivative of formula (1)                    
     wherein R 1  is COOH, COOR 6  etc.; A is alkylene etc.; R 2  is alkyl, alkenyl, alkynyl etc.; B is carbocyclic ring or heterocyclic ring; R 4  is alkyl, cycloalkyl etc.; R 6  is carbocyclic ring or heterocyclic ring; 
     or non-toxic salts thereof, a process for the preparation thereof and a pharmaceutical agent comprising the same as active ingredient. 
     The compound of the formula (I) can bind to Prostaglandin E 2  receptors, especially, EP 3  receptor and/or EP 4  receptor and show the antagonizing activity, and useful for the prevention and/or treatment of disease, for example, pain, allergy, Alzheimer&#39;s disease, cancer.

TECHNICAL FIELD

The present invention relates to carboxylic acid derivatives. Morespecifically, the present invention relates to a carboxylic acidderivative of formula (I)

wherein all symbols are as hereinafter defined, a process for thepreparation thereof and a pharmaceutical agent comprising the same asactive ingredient.

BACKGROUND

Prostaglandin E₂ (PGE₂) has been known as a metabolite in thearachidonic acid cascade. It has been known that PGE₂ possessescyto-protective activity, uterine contractile activity, a pain-inducingeffect, a promoting effect on digestive peristalsis, an awaking effect,a suppressive effect on gastric acid secretion, hypotensive activity,and diuretic activity.

In the recent study, it was found that PGE₂ receptor was divided intosome subtypes, which possesses different physical roles from each other.At present, four receptor subtypes are known and they are called EP₁,EP₂, EP₃ and EP₄ respectively (J. Lipid Mediators Cell Signaling 12,379-391 (1995)).

Among these subtypes, EP_(a) receptor was believed to be involved insignal transduction of peripheral nerve, control of exothermal reactionin central nerve, formation of memory by expressing in cerebral neuron,vascularization, reabsorption of urine by expressing in renal tubular,uterine contraction, production of ACTH, platelet aggregation. Besides,it was expressed in vascular smooth muscle, heart and gastrointestinaltract also. EP₄ recptor was believed to be involved in suppression ofTNF-α production and induction of IL-10 production.

So the compounds which can bind to EP₃ receptor and/or EP₄ receptorstrongly and show the antagonizing activity, are useful for theprevention and/or treatment of diseases induced by excess activation ofEP₃ receptor and/or EP₄ receptor, for example, pain such as cancerouspain, fractural pain, pain following surgical and dental procedures;allodynia, hyperalgesia, pruritus, urticaria, atopic dermatitis, contactdermatitis, allergic conjunctivitis, various symptoms by treating withdialysis, asthma, rhinitis, sneeze, urinary frequency, neurogenicbladder, urinary disturbance, ejaculatory failure, defervescence,systemic inflammatory response syndrome, learning disturbance,Alzheimer's disease, cancer such as formulation of cancer, growth ofcancer and metastasis of cancer; retinopathy, patch of red, scald, burn,burn by steroid, renal failure, nephropathy, acute nephritis, chronicnephritis, abnormal blood levels of electrolytes, threatened prematuredelivery, abortion threatened, hypermenorrhea, dysmenorrhea, uterinefibroids, premenstrual syndrome, reproductive disorder, stress, anxietydisorders, depression, psychosomatic disorder, mental disorder,thrombosis, embolism, transient ischemia attack, cerebral infarction,atheroma, organ transplant, myocardial infarction, cardiac failure,hypertension, arteriosclerosis, circulatory failure and circulatoryfailure induced ulcer, neuropathies, vascular dementia, edema, variousarthritis, rheumatism, diarrhea, constipation, disorder of biliousexcretion, ulcerative colitis, Crohn's disease and/or bone diseases suchas osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal boneformation; cancer such as formation of cancer, proliferation of cancer,metastasis of cancer to organs and to bones and hypercalcemia inducedmetastasis to bones of cancer; systemic granuloma, immunologicaldiseases such as ALS, multiple sclerosis, Sjoegren's syndrome, systemiclupus erythematosus, AIDS; allergy such as conjunctivitis, rhinitis,contact dermatitis, psoriasis; atopic dermatitis, asthma, pyorrhea,gingivitis, periodontitis, neuronal cell death, Alzheimer's disease'sdisease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis,renal failure, myocardial ischemia, Kawasaki disease, scald, ulcerativecolitis, Crohn's disease, multiple organ failure etc. Moreover, EP₄ isthought to be involved in sleeping disorder and platelet aggregation, sothe compounds are considered to be useful.

DISCLOSURE OF THE INVENTION

The present inventors have energetically studied to find the compoundwhich bind to PGE₂ receptor, EP₃ and/or EP₄ receptor specifically andshow an inhibitory activity against it, to find out that the carboxylicacid derivatives of formula (I) achieve the purpose and completed thepresent invention.

This invention was relates to

(1) a carboxylic acid derivative of formula (I)

wherein R¹ is COOH, COOR⁶, CH₂OH, CONHSO₂R⁷ or CONR⁸R⁹,

R⁶ is C1-6 alkyl, (C1-4 alkylene)—R¹⁶,

R⁷ is (1) C1-4 alkyl, or (2) substituted by 1-2 of substitutes selectedform C1-4 alkyl, C1-4 alkoxy and halogen atom or unsubstituted (2-1)C6-12 mono- or bi-carbocyclic ring or (2-2) 5-15 membered mono- orbi-heterocyclic ring containing at least one of hetero atom selectedfrom nitrogen, oxygen and sulfur, or (3) C1-4 alkyl substituted by theabove substituents or unsubstituted carbocyclic ring or heterocyclicring,

R⁸ and R⁰ each independently, is hydrogen or C1-4 alkyl,

R¹⁶ is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR⁸R⁹,

A is C1-6 alkylene or —(C1-3 alkylene)_(w)—G—(C1-3 alkylene)—,

w is 0 or 1,

G is oxygen, sulfur or NR¹⁰,

R¹⁰ is hydrogen or C1-4 alkyl,

R² is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom,CF₃, cyano, nitro, hydroxy, NR¹¹R¹², CONR¹¹R¹², SO₂NR¹¹R¹², or—S(O)_(x)—(C1-6)alkyl,

m is 0, 1 or 2, when m is 2, then two R² may be same or difference,

R¹¹ and R¹² each independently, hydrogen or C1-4 alkyl,

x is 0, 1 or 2,

B ring is C5-7 mono-carbocyclic ring or 5-7 membered mono-heterocyclicring containing at least one of nitrogen, oxygen and sulfur,

R³ is hydrogen or C1-4 alkyl,

R⁴ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) C3-6cycloalkyl, (5) hydroxy, (6) C1-4 alkoxy, (7) C1-4 alkoxy(C1-4)alkoxy,or (8) C1-8 alkyl substituted by 1-2 of substitutes selected fromhalogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl andC3-6 cycloalkyl,

R⁵ is substituted by 1-2 of R¹³ or unsubstituted C5-10 mono- orbi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ringcontaining at least one of nitrogen, oxygen and sulfur,

R¹⁸ is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF₃, cyano, C1-4alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, —(C1-4alkylene)_(y)-J—(C1-8 alkylene)_(x)—R¹⁴, benzoyl or thiophenecarbonyland two R¹³ may be same or difference,

y is 0 or 1,

z is 0 or 1,

R¹⁴ is phenyl or pyridyl,

J is oxygen, S(O)_(t) or NR¹⁵,

t is 0, 1 or 2,

R¹⁶ is hydrogen, C1-4 alkyl or acetyl;

or non-toxic salts,

(2) a process of the preparation thereof, and

(3) a pharmaceutical agent comprising the same as active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, C1-4 alkyl is methyl, ethyl, propyl, butyl andisomers thereof.

In the present invention, C1-6 alkyl is methyl, ethyl, propyl, butyl,pentyl, hexyl and isomers thereof.

In the present invention, C1-8 alkyl is methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and isomers thereof.

In the present invention, C2-6 alkenyl is ethenyl, propenyl, butenyl,pentenyl, hexenyl and isomers thereof.

In the present invention, C2-8 alkenyl is ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.

In the present invention, C2-6 alkynyl is ethynyl, propynyl, butynyl,pentynyl, hexynyl and isomers thereof.

In the present invention, C2-8 alkynyl is ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.

In the present invention, C1-4 alkoxy is methoxy, ethoxy, propoxy,butoxy and isomers thereof.

In the present invention, C1-6 alkoxy is methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy and isomers thereof.

In the present invention, C1-4 alkoxy(C1-4)alkyl is, for example,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl butoxymethyl andisomers thereof.

In the present invention, C1-4 alkoxy(C1-4)alkoxy is, for example,methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxybutoxy,ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, ethoxybutoxy and isomersthereof.

In the present invention, C1-4 alkoxycarbonyl is methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isomers thereof.

In the present invention, C1-2 alkylene is methylene, ethylene andisomers thereof.

In the present invention, C1-3 alkylene is methylene, ethylene,trimethylene and isomers thereof.

In the present invention, C1-4 alkylene is methylene, ethylene,trimethylene, tetramethylene and isomers thereof.

In the present invention, C1-6 alkylene is methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof.

In the present invention, C1-8 alkylene is methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene and isomers thereof.

In the present invention, C2-4 alkylene is ethylene, trimethylene,tetramethylene and isomers thereof.

In the present invention, C3-6 cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

In the present invention, halogen atom is fluoride, chloride, bromideand iodide.

In the present invention, C6-12 mono- or bi-carbocyclic ring is C6-12unsaturated, or partially or fully saturated mono- or bi-carbocyclicring, for example, cyclohexane, cycloheptane, cyclohexene, benzene,indene, naphthalene, indan, tetrahydronaphthalene.

In the present invention, 5-15 membered mono- or bi-heterocyclic ringcontaining at least one of hetero atom selected from nitrogen, oxygenand sulfur is 5-15 membered unsaturated, or partially or fully saturatedmono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 ofoxygen(s), 1 of sulfur, 1 of nitrogen and 1 of oxygen, or 1 of nitrogenand 1 of sulfur, for example, furan, thiophene, pyrrole, oxazole,isoxazole, isothiazole, imidazole, pyrazole, tetrazole, pyridine,pyrimidine, pyrazine, benzofuran, benzothiophene, benzothiazole, indole,benzoxazole, benzimidazole, benzodioxane, thienopyridine, indoline,isoindoline, 1,3-dioxaindan, chroman, isochroman, quinoline,isoquinoline, quinazoline, quinoxaline.

In the present invention, C5-7 mono-carbocyclic ring is C5-7unsaturated, partially or fully saturated mono-carbocyclic ring, forexample, cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, benzene.

In the present invention, 5-7 membered mono-heterocyclic ring containingat least one of hetero atom selected from nitrogen, oxygen and sulfur is5-7 membered mono-heterocyclic ring containing 1-2 of nitrogen(s), 1-2of oxygen(s) and/or 1 of sulfur, for example, furan, thiophene, pyrrole,oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine,pyrimidine, pyrazine, azepine.

In the present invention, C5-6 mono-carbocyclic ring is C5-6unsaturated, partially or fully saturated mono-carbocyclic ring, forexample, cyclopentane, cyclohexane, cyclopentene, cyclohexene, benzene.

In the present invention, 5-6 membered mono-heterocyclic ring containing1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur, for example, furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyridine, pyrimidine, pyrazine.

In the present invention, C5-10 mono- or bi-carbocyclic ring is C5-10unsaturated, partially or fully saturated mono- or bi-carbocyclic ring,for example, cyclopentane, cyclohexane, cycloheptane, benzene, indan,indene, naphthalene, and tetrahydronaphthalene.

In the present invention, 5-10 membered mono- or bi-heterocyclic ringcontaining at least one of hetero atom selected from nitrogen, oxygenand sulfur is 5-10 membered unsaturated, partially or fully saturatedmono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 ofoxygen(s), 1 of sulfur, 1 of nitrogen and 1 of oxygen or 1 of nitrogenand 1 of sulfur, for example, furan, thiophene, pyrrole, oxazole,isoxazole, thiazole, isothiazole, imidazole, pyrazole, tetrazole,pyridine, pyrimidine, pyrazine, benzofuran, benzothiophene,benzothiazole, indole, benzoxazole, benzimidazole, benzodioxane,thienopyridine, indoline, isoindoline, 1,3-dioxaindane, chroman,isochroman, quinoline, isoquinoline, quinazoline, quinoxaline.

In the present invention, 5-10 membered mono- or bi-heterocyclic ringcontaining 1-2 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur is5-10 membered unsaturated, partially or fully saturated mono- orbi-heterocyclic ring containing 1-2 of nitrogen(s), 1-2 of oxygen(s), 1of sulfur, 1 of nitrogen and 1 of oxygen or 1 of nitrogen and 1 ofsulfur, for example, furan, thiophene, pyrrole, oxazole, isoxazole,thiazole, isothiazole, imidazole, pyrazole, pyridine, pyrimidine,pyrazine, benzofuran, benzothiophene, benzothiazole, indole,benzoxazole, benzoimidazole, benzodioxane, indoline, isoindoline,1,3-dioxaindane, chroman, isochroman, quinoline, isoquinoline,quinazoline, quinoxaline.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl and alkylene groupsinclude straight-chain and also branched-chain ones. In addition,isomers in double bond, ring, fused ring (E-, Z-, cis-, trans-isomer),isomers generated from asymmetric carbon atom(s) (R-, S-, α-, β-isomer,enantiomer, diastereomer), optically active isomers having opticalrotation (D-, L-, d-, l-isomer), polar compounds separated bychromatography (more polar compound, less polar compound), equilibriumcompounds, mixtures thereof at arbitrary ratios and racemic mixtures areincluded in the present invention.

More preferably compound of the present invention of formula (1) is thecompound which is

R¹ is COOH, COOR⁶, CH₂OH, CONHSO₂R⁷ or CONR⁸R⁹,

R⁶ is C1-6 alkyl, (C1-4 alkylene)—R¹⁶,

R⁷ is (1) C1-4 alkyl, or (2) substituted by 1-2 of substitutes selectedform C1-4 alkyl, C1-4 alkoxy and halogen atom or unsubstituted (2-1)C6-12 mono- or bi-carbocyclic ring or (2-2) 5-15 membered mono- orbi-heterocyclic ring containing at least one of hetero atom selectedfrom nitrogen, oxygen and sulfur, or (3) C1-4 alkyl substituted by theabove substituted or unsubstituted carbocyclic ring or heterocyclicring,

R⁸ and R⁹ each independently, is hydrogen or C1-4 alkyl,

R¹⁰ is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CON⁸R⁹,

A is C2-4 alkylene or —(C1-2 alkylene)_(w)-G—(C1-2 alkylene)-,

w is 0 or 1,

G is oxygen, sulfur or NR¹⁰,

R¹⁰ is hydrogen or C1-4 alkyl,

R² is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom,CF₃ or cyano,

B ring is C5-6 mono-carbocyclic ring or 5-6 membered mono-heterocyclicring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur,

m is 0 or 1,

R³ is hydrogen or C1-4 alkyl,

R⁴ is C1-8 alkyl, C3-6 cycloalkyl or C1-8 alkyl substituted by 1-2 ofC3-6 cycloalkyl,

R⁵ is substituted by 1-2 of R¹³ or unsubstituted, C5-10 mono- orbi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ringcontaining 1-2 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur,

R¹³ is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF₃, cyano or —(C1-4alkylene)_(y)-J—(C1-8 alkylene)_(Z)—R¹⁴,

y is 0,

J is oxygen,

z is 1,

R¹⁴ is phenyl;

or non-toxic salts thereof.

In the present compound of formula (I), a preferably R¹ is COOH, COOR⁶,CH₂OH, CONHSO₃R⁷ or CONR⁸R⁹, in which a preferably R⁷ is (1) C1-4 alkyl,(2) substituted by 1-2 of substitutes selected from C1-4 alkyl, C1-4alkoxy and halogen atom, or unsubstituted cyclohexane, cycloheptane,cyclohexane, benzene, indene, naphthalene, indan, tetrahydronaphthalene,furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, tetrazole, pyridine, pyrimidine, pyrazine,benzofuran, benzothiophene, benzothiazole, indole, benzoxazole,benzoimidazole, benzodioxane, thienopyridine, indoline, isoindoline,1,3-dioxaindan, chroman, isochroman, quinoline, isoquinoline,quinoxaline or (3) C1-2 alkyl substituted by the above ring described in(2), especially preferably R⁷ is (1) C1-4 alkyl, (2) substituted by 1-2of substitutes selected from C1-4 alkyl, C1-4 alkoxy and halogen atom,or unsubstituted benzene, thiophene, oxazole, isoxazole, thiazole,isothiazole, pyridine or (3) C1-2 alkyl substituted by the above ringdescribed in (2), and the other symbols are as hereinbefore defined.

In the compound of the present invention, concrete B ring iscyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene,benzene, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole,isothiazole, imidazole, pyridine, pyrimidine, pyrazine, and azepine.Preferably B ring is cyclopentane, cyclohexane, benzene, furan,thiophene, pyrrole, imidazole, pyridine, pyrimidine, pyrazine,especially preferably, cyclohexane, benzene, thiophene, pyridine.

In the compound of the present invention, concrete R⁵ is substituted by1-2 of R¹³, wherein R¹³ is as hereinbefore defined; or unsubstitutedcyclopentane, cyclohexane, cycloheptane, benzene, indan, indene,naphthalene, tetrahydronaphthalene, furan, thiophene, pyrrole, oxazole,isoxazole, thiazole, isothiazole, imidazole, pyrazole, tetrazole,pyridine, pyrimidine, pyrazine, benzofuran, benzothiophene,benzothiazole, indole, benzoxazole, benzoimidazole, benzodioxane,thienopyridine, indoline, isoindoline, 1,3-dioxaindan, chroman,isochroman, quinoline, isoquinoline, quinazoline, quinoxaline.Preferably R⁵ is substituted by 1-2 of R¹³, wherein R¹³ is ashereinbefore defined; or unsubstituted cyclohexane, benzene,naphthalene, tetrahydronaphthalene, furan, thiophene, pyrrole, pyridine,pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzodioxane,quinoline, isoquinoline, quinazoline, quinoxaline, especiallypreferably, substituted by 1-2 of R¹³, wherein R¹³ is as hereinbeforedefined; or unsubstituted benzene, naphthalene, tetrahydronaphthalene,benzofuran, benzothiophene, indole, benzodioxane, quinoline.

In the compounds of the present invention of formula (I), the compoundsdescribed in examples are preferable.

Salt

The compound of the present invention of formula (I) may be convertedinto a corresponding salt by known methods. In the present invention,salts are salts of alkali metals, salts of alkaline-earth metals,ammonium salts, pharmaceutically acceptable organic amines, acidaddition salts and hydrates. Non-toxic and water-soluble salts arepreferable.

Appropriate salts are, salts of alkali metals such as potassium, sodium,etc.; salts of alkaline-earth metals such as calcium, magnesium, etc.;ammonium salts, pharmaceutically acceptable organic amines such astetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine, etc.

Appropriate acid addition salts are, salts of inorganic acids such ashydrochloride, hydrobromide, sulfate, phosphate, nitrate; salts oforganic acids e.g. acetate, trifluoroacetate, lactate, tartrate,oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate,ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate,glucuronate, gluconate.

The compounds of formulae (I) and salts thereof may be converted intothe corresponding hydrates by conventional means.

Preparation of the Compound of the Present Invention

The present compound of formula (a) may be prepared, for example, by thefollowing method.

(1) In the compound of formula (I), wherein R¹ is COOH, that is thecompound of formula (Ia)

 wherein all symbols are as hereinbefore defined;

may be prepared by subjecting to hydrolysis under an alkaline conditionsthe compound of formula (Ib-1)

 wherein R⁶⁻¹ is C1-6 alkyl and the other symbols are as hereinbeforedefined.

Hydrolysis under alkaline conditions is known, for example, it iscarried out in a water-miscible organic solvent (e.g. methanol, ethanol,tetrahydrofuran, dioxane or a mixture thereof), using an aqueoussolution of an alkali (e.g. sodium hydroxide, potassium hydroxide orpotassium carbonate) at −10-90° C.

(2) In the compound of formula (I), wherein R¹ is CH₂OH, that is thecompound of formula (Ic)

 wherein all symbols are as hereinbefore defined;

may be prepared by subjecting to reduction the compound of formula (Ia).

Reduction reaction is known, for example, it is carried out in organicsolvent (e.g. tetrahydrofuran, diglyme), using borane complex at 0-50°C.

(3) In the compound of formula (I), wherein R¹ is CONHSO₂R⁷ and CONR⁸R⁹,that is the compound of formula (Id)

wherein all symbols are as hereinbefore defined; and the compound offormula (Ie)

 wherein all symbols are same as hereinbefore defied;

may be prepared by subjecting to amidation reaction the compound offormula (Ia) and the compound of formula (II-1)

H₂NSO₂R⁷  (II-1)

wherein all symbols are as hereinbefore defined; or the compound offormula (II-2)

HNR⁸R⁹  (II-2)

wherein all symbols are as hereinbefore defined.

Amidation reaction is known, for example, it is carried out in anorganic solvent (e.g. tetrahydrofuran, methylene chloride, chloroform,benzene, acetone, acetonitrile, diethyl ether or a mixture thereof), inthe presence or absence of a tertiary amines (e.g.dimethylaminopyridine, pyridine, triethylamine), using a condensingagent (e.g. 1,3-dicyclohexylcarbodiimide(DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC),2-chloro-1-methylpyridium iodide) or acyl halide (e.g. oxalyl chloride,thionyl chloride, phosphorus oxychloride) at 0-50° C.

(4) The compound of formula (Ib-1) may be prepared by subjecting toamidation reaction the compound of formula (III)

wherein all symbols are as hereinbefore defined; and the compound offormula (IV)

 wherein all symbols are as hereinbefore defined.

Amidation reaction is carried out by the above method.

(5) In the compound of formula (I), wherein R¹ is COOR⁶⁻², in which R⁶⁻²is —(C1-4 alkylene)-R¹⁸; that is the compound of formula (Ib-2)

 wherein all symbols are as hereinbefore defined;

may be prepared by reacting the compound of formula (Ia) with thecompound of formula (V)

X—(C1-4 alkylene)-R¹⁶  (V)

wherein X is halogen atom and the other symbols are as hereinbeforedefined.

This reaction is known, for example, it is carried out in an organicsolvent (e.g. dimethylformamide, tetrahydrofuran, acetone,acetonitrile), using potassium carbonate, sodium carbonate or sodiumhydride, at 0-50° C.

The compounds of formula (II-1), (II-2), (III), (IV) and (V) may beknown per se, or may be prepared by known methods with ease. Forexample, among the compound of formula (III), 4-(2-aminopheny)butyricacid methyl ester is described in the document of SyntheticCommunications, 26(18), 3443-3452 (1996).

The compound of formula (III) may be prepared according to the followingreaction scheme A. Besides, a part of the compound of formula (III) maybe also prepared according to the following reaction scheme B.

In above schemes

A¹ is C1-6 alkylene,

G¹ is OH, SH, NHR¹⁰,

G² is S, NR10,

Ac is acetyl,

the other symbols are as hereinbefore defined.

Besides, the compound of formula (I) may be also prepared according tothe following reaction schemes C, D-1 or D-2.

In above schemes

AA is C2-6 alkenylene,

A² is C2-6 alkylene,

W¹ is a protecting group of hydroxy,

W²is a protecting group of amino,

the other symbols are as hereinbefore defined.

And the starting materials and reagents may be known per se or may beprepared by known methods.

The desired compound having hydroxy or amino may be easily prepared by acorresponding method selected from deprotection reactions such asdeprotection under alkaline conditions, deprotection under acidicconditions and hydrogenolysis, using the compound having protectedhydroxy or protected amino by a corresponding protecting group.

Methoxymethyl, tetrahydopyranyl, t-butyldimethylsilyl, acetyl, benzylmay be used as protecting groups for hydroxy. As protecting groups,other groups, which can be removed easily and selectively other than theabove protecting groups, are also preferred.

Benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl may be used asprotecting groups for amino. As protecting groups, other groups, whichcan be removed easily and selectively other than the above protectinggroups, are also preferred. For example, the groups described in T. W.Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991, maybe used.

In each reaction in the present specification, reaction products may bepurified by conventional purification techniques, e.g. by distillationunder atmospheric or reduced pressure, by high performance liquidchromatography, by thin layer chromatography or by column chromatographyusing silica gel or magnesium silicate; or by washing or byrecrystallization. Purification may be carried out after each reactionor after a series of reactions.

[Pharmacological Activities]

The compounds of the present invention of formula (I) bind strongly andshow an antagonizing activity on the PGE₂ receptor, especially, EP₈and/or EP₄ receptor.

For example, in a standard laboratory test, such effects of the compoundof the present invention were confirmed by binding assay using the cellexpressing the prostanoid receptor subtypes.

(i) Binding Assay Using Cell Expressing the Prostanoid Receptor Subtypes

The preparation of membrane fraction was carried out according to themethod of Sugimoto et al [J. Biol. Chemical, 267, 6463-6466 (1992)],using CHO cell expressing prostanoid receptor subtypes (mouse EP₁, EP₂,EP_(3α), and EP₄).

The standard assay mixture containing membrane fraction (50 μL),[³H]—PGE₂ in a final volume of 150 μL was incubated for 1 hour at roomtemperature. The reaction was terminated by addition of 3 mL of ice-coldbuffer. The mixture was rapidly filtered through a glass filter (GF/B)under reduced pressure. The radioactivities associated with the filterswere measured by liquid scintillation counter.

Kd and Bmax values were determined from Scatchard plots [Ann. N. Y.Acad. Sci. 51, 660(1949)]. Non-specific binding was determined as theamount bound in the presence of an excess (2.5 μM of unlabeled PGE₂. Inthe experiment for competition of specific [³H]—PGE₂ binding assay,[³H]—PGE₂, was added at a concentration of 2.5 nM and a test compound ofthe present invention was added at various concentrations. The followingbuffer was used in all reactions.

Buffer: 10 mM potassium phosphate (pH 6.0), 1 mM EDTA, 10 mM MgCl₂, 0.1M NaCl.

The inhibition constant (Ki) (μM) of each compound was calculated by thefollowing equation. The results are shown in Table 1.

Ki=IC₅₀/(1+([C]/Kd))

TABLE 1 Ki(μM) Example EP₁ EP₂ EP₃ EP₄ No. receptor receptor receptorreceptor 2 >10 >10 2.4 0.3 (ii) EP₃ antagonizing activity assay usingthe cell expressing the prostanoid receptor subtypes

The preparation of CHO cell expressing mouse EP₃ receptor subtype wascarried out according to the method of Sugimoto et al [J. Biol. Chem.267, 6463-6466 (1992)]. The cells were cultured in 96-well microplates(10⁴ cells/well) for two days before experiments. After washing eachwell with 100 μL of PBS, Fura-2AM was added to taken in the cell for 60mutes. After washing each well with HEPES, then a test compound and PGE₂(10 nM) were added at 37° C. A variation of intracellular calciumconcentration was measured. Namely, excitation with a wavelength of340/380 nm carried out, and fluorescence of 510 nm was measured, then aratio of fluorescence intensity was calculated. By the way, anantagonizing activity of a test compound was calculated as inhibitoryrate on the condition using PGE₂ (10 nM) as an agonist, and then IC₅₀value was calculated.

(ii) EP₄ Antagonizing Activity Assay Using the Cell Expressing theProstanoid Receptor Subtypes

The preparation of CHO cell expressing mouse EP₄ receptor subtype wascarried out according to the method of Nishigaki et al [FEBS lett., 364,339-341(1995)]. The cells were cultured in 24well microplates (10⁵cells/well) for two days before experiments. After washing each wellwith 500 μL of MEM (MEM essential medium), thereto was added 450 μL ofassay medium MEM containings 1 mmol/L IBMX, 1% BSA), and the mixture wasincubated for 10 minutes at 37° C. Then PGE₂ alone or a combination witha test compound (50 μL) were added, and the mixture was incubated for 10minutes at 37° C. And reaction was terminated by addition of ice-coldTCA (10% w/v, 500 μL). This reaction mirture was freezed once (−80° C.)and thawed, and cells were harvested using a scraper. Aftercentrifugation (13,000 r.p.m., for 3 minutes), cAMP content was measuredusing cAMP assay kit. That is, the supernatant (125 μL) was diluted with500 μL of [¹²⁵I]-cAMP assay kit buffer (Amersham), and mixed with 0.5mol/L tri-n-octylamine/chloroform solution (1 mL) was med. After removalof TCA from chloroform layer, cAMP content in the aqueous layer wasquantified according to the method of kit manuals.

An antagonizing activity of compound (IC₅₀ value) was calculated as aninhibitory rate on the condition using 100 nM PGE₂ as an agonist. Thisconcentration of PGE₂ served a submaximal effect on cAMP production.

As mentioned above, it was clear that the compounds of the presentinvention show a strong antagonizing activity on the EP₃ and/or EP₄subtype receptor.

[Toxicity]

The toxicity of the compounds of the formula (I) of the presentinvention is very low and therefore, it is confirmed that thesecompounds are safe for use as medicine.

[Application to Pharmaceuticals]

The compounds of the present invention of the formula (I) can bind andshow the antagonizing activity on the PGE₂ receptor. Particularly, theybind to EP₃ receptor and/or EP₄ receptor strongly and show theantagonizing activity, are useful for the prevention and/or treatment ofdiseases induced by excess activation of EP₃ receptor and/or EP₄receptor, for example, pain such as pain such as cancerous pain,fractural pain, pain following surgical and dental procedures;allodynia, hyperalgesia, pruritus, urticaria, atopic dermatitis, contactdermatitis, allergic conjunctivitis, various symptoms by treating withdialysis, asthma, rhinitis, sneeze, urinary frequency, neurogenicbladder, urinary disturbance, ejaculatory failure, defervescence,systemic inflammatory response syndrome, learning disturbance,Alzheimer's disease, cancer such as formulation of cancer, growth ofcancer and metastasis of cancer; retinopathy, patch of red, scald, burn,burn by steroid, renal failure, nephropathy, acute nephritis, chronicnephritis, abnormal blood levels of electrolytes, threatened prematuredelivery, abortion threatened, hypermenorrhea, dysmenorrhea, uterinefibroids, premenstrual syndrome, reproductive disorder, stress, anxietydisorders, depression, psychosomatic disorder, mental disorder,thrombosis, embolism, transient ischemia attack, cerebral infarction,atheroma, organ transplant, myocardial infarction, cardiac failure,hypertension, arteriosclerosis, circulatory failure and circulatoryfailure induced ulcer, neuropathies, vascular dementia, edema, variousarthritis, rheumatism, diarrhea, constipation, disorder of biliousexcretion, ulcerative colitis, Crohn's disease and/or bone diseases suchas osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal boneformation; cancer such as formation of cancer, proliferation of cancer,metastasis of cancer to organs and to bones and hypercalcemia inducedmetastasis to bones of cancer; systemic granuloma, immunologicaldiseases such as ALS, multiple sclerosis, Sjoegren's syndrome, systemiclupus erythematosus, AIDS; allergy such as conjunctivitis, rhinitis,contact dermatitis, psoriasis; atopic dermatitis, asthma, pyorrhea,gingivitis, periodontitis, neuronal cell death, Alzheimer's disease'sdisease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis,renal failure, myocardial ischemia, Kawasaki disease, scald, ulcerativecolitis, Crohn's disease, multiple organ, sleeping disorder and plateletaggregation.

For the purpose described above, the compounds of formula (I), of thepresent invention, non-toxic salts thereof may be normally administeredsystemically or topically, usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment, etc. In the humanadult, the doses per person at a time are generally from 0.1 mg to 100mg, by oral administration, up to several times per day, and from 0.01mg to 10 mg, by parenteral administration (preferably intravenousadministration), up to several times per day, or continuousadministration between 1 and 24 hours per day into vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases wherein doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid compositions, liquid compositions or othercompositions for oral administration, injections, liniments orsuppositories for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) may beadmixed with vehicles (such as lactose, mannitol, glucose,microcrystalline cellulose, starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate),disintegrants (such as cellulose calcium glycolate), lubricants (such asmagnesium stearate), stabilizing agents, and solution adjuvants (such asglutamic acid or aspartic acid) and prepared according to methods wellknown in normal pharmaceutical practice. The solid forms may, ifdesired, be coated with coating agents (such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions and emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulsified into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulsified into solvent(s). The solvents may include distilled water forinjection, physiological salt solution, vegetable oil, propylene glycol,polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.

Injections may comprise some additives, such as stabilizing agents,solution adjuvants (such as glutamic acid, aspartic acid orPOLYSORBATE80 (registered trade mark)), suspending agents, emulsifyingagents, soothing agent, buffering agents, preservative. They may besterilized at a final step, or may be prepared and compensated accordingto sterile methods. They may also be manufactured in the form of sterilesolid forms, for example, freeze-dried products, which may be dissolvedin sterile water or some other sterile diluent(s) for injectionimmediately before use.

Other forms for parenteral administration include liquids for externaluse, ointments and endermic liniments, inhalations, sprays,suppositories and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by methodsknown per se. Sprays may comprise additional substances other thandiluents, such as stabilizing agents (such as sodium sulfate), isotonicbuffers (such as sodium chloride, sodium citrate or citric acid). Forpreparation of such sprays, for example, the method described in theU.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.

Best Mode for Carrying Out the Invention

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parenthesis show the eluting or developing solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents used inmeasurement.

In the structure, Boc is t-butoxycarbonyl.

REFERENCE EXAMPLE 1 4(2-nitrophenyl)butanoic acid methyl ester

To a suspension of zinc powder (851 mg) in tetrahydrofuran (THF; 4 ml),a catalytic amount of chloromethylsilane under reflux. A solution of4-iodebutanoicacid methyl ester (1.98 g) in THF (5 ml) was droppedslowly into this suspension and refluxed 3 hours. The mixture was cooledby allowing to stand and so a solution of 3-carbomethoxypropyl-zinc (II)iodide (alkyl zinc) in THP was prepared.

After deaeration, bis(dibenzylideneacetone)palladium (333 mg),1,1′-bis(dipheylphosphino)ferrocene (321 mg) and the above preparedsolution of alkyl zinc in THF were added to a solution of1-iode-2-nitrobenzene (1.442 g) in THF (6 ml), and the mixture wasstirred for 1.5 hours at 50° C. The reaction mixture was cooled. Asaturated aqueous solution of ammonium chloride was added to themixture. The mixture was extracted with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel to give the titlecompound (784 mg) having the following physical data.

TLC: Rf 0.47 (n-hexane:ethyl acetate=4:1);

NMR(200 MHz, CDCl₃): δ7.91 (m, 1H), 7.53 (m, 1H), 7.42-7.31 (m, 2H),3.69 (s, 3H), 2.93 (t, J=7.6 Hz, 2H), 2.41 (t, J=7.4 Hz, 2H), 2.01 (m,2H).

REFERENCE EXAMPLE 2 4-(2-aminophenyl)butanoic acid methyl ester

Under an atmosphere of argon, 10% palladium carbon (80 mg; 10 w %) wasadded to a solution of the compound prepared in reference example 1 (780mg) in methanol (5 ml). The mixture was stirred for 3 hours at roomtemperature under atmosphere of hydrogen gas. The reaction mixture wasfiltered through celite (trademark). The filtrate was concentrated. Theresidue was purified by column chromatography on silica gel to give thetitle compound (567 mg) having the following physical data.

TLC: Rf 0.36 (n-hexane:ethyl acetate=3:1);

NMR(200 MHz, CDCl₃): δ7.07-6.98 (m, 2H), 6.74-6.65 (m, 2H), 3.80 (br,2H), 3.69 (s, 3H), 2.53 (m, 2H), 2.41 (t, J=6.9 Hz, 2H), 1.92 (m, 2H).

EXAMPLE 1 4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid methylester

To a solution of the compound prepared in reference example 2 (300 mg)and pyridine (0.25 ml) in methylene chloride (1 ml), a solution of2-(1-naphthyl)propionyl chloride (389 mg) in methylene chloride (2 ml)was added under cooling with ice. The mixture was stirred for 3 hours atroom temperature. To the reaction mixture, a saturated aqueous solutionof sodium bicarbonate was added. The mixture was extracted with ethylacetate, The organic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate andconcentrated. The crude crystals was recrystallized with ethylacetate/hexane to give the title compound (441 mg) having the followingphysical data.

TLC Rf 0.40 (toluene:ethyl acetate=9:1);

NMR(200 MHz, CDCl₃): δ8.20 (m, 1H), 7.98-7.80 (m, 3H), 7.66 (m, 1H),7.60-7.46 (m, 3H), 7.38 (brs, 1H), 7.18 (m, 1H), 7.02-6.97 (m, 2H), 4.65(q, J=7.0 Hz, 1H), 3.58 (s, 3H), 2.06-1.90 (m, 4H), 1.82 (d, J=7.0 Hz,3H), 1.32 (m, 2H).

EXAMPLE 1(1)-1(2)

The following compounds were obtained by the same procedure as a seriesof reactions of Reference example 1→Reference example 2→Example 1, usingcorresponding compounds.

EXAMPLE 1(1) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]bitanoicacid methyl ester

TLC: Rf 0.40 (n-hexane:ethyl acetate 2:1);

NMR(300 MHz, CDCl₃): δ8.50 (d, J=1.5 Hz, 1H), 8.18 (m, 1H), 7.90 (m,1H), 7.84 (d, J=8.1 Hz, 1H), 7.81 (br, 1H), 7.64 (m, 1H), 7.58 7.48 (m,3H), 7.27 (dd, J=7.8, 1.5 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 4.72 (q,J=7.2 Hz, 1H), 3.57 (s, 3H), 2.11 (m, 2H), 2.03 (m, 2H), 1.80 (d, J=7.2Hz, 3H), 1.38 (m, 2H).

EXAMPLE 1(2) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid butyl ester

TLC: Rf 0.49 (n-hexane:ethyl acetate=3:1);

NMR(300 MHz, CDCl₃): δ8.51 (d, J=1.8 Hz, 1H;), 8.18 (m, 1H), 7.96 7.80(m, 3H), 7.64 (dd, J=7.2, 0.9 Hz, 1H), 7.57-7.47 (m, 3H), 7.27 (dd,J=7.8, 1.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 4.74 (q, J=7.2 Hz, 1H), 4.00(m, 1H), 3.88 (m, 1H), 2.15 (m, 2H), 2.05 (m, 2H), 1.79 (d, J=7.2 Hz,3H), 1.55 (m, 2H), 1.35 (m, 4H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 2

4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid

To a solution of the compound prepared in Example 1 (436 mg) inmethanol/dioxane (1:2; 6 ml), 2M aqueous solution of sodium hydroxide (3ml) was added, and the mixture was stirred for 2 hours at 50° C. Thereaction mixture was acidified by adding hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of sodium chloride, driedover magnesium sulfate and concentrated. The crude crystal was washedwith ethyl acetate to give the title compound (288 mg) having thefollowing physical data.

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:2);

NMR(300 MHz, d₆-DMSO): δ12.04 (brs, 1H), 9.46 (brs, 1H), 8.31 (d, J=8.4Hz, 1H), 7.94 (m, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.62-7.47 (m, 4H), 7.27(m, 1H), 7.19-7.07 (m, 3H), 4.69 (q, J=6.9 Hz, 1H), 2.43 (m, 2H), 2.02(t, J=7.2 Hz, 2H), 1.59 (d, J=6.9 Hz, 3H), 1.56 (m, 2H).

EXAMPLE 2(1)-2(24)

The following compounds were obtained by the same procedure as a seriesof reactions of Reference example 1→Reference example 2→Example1→Example 2, using corresponding compounds.

EXAMPLE 2(1) 4-[2-[2-(4-pentylphenyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.54 (chloroform:methanol=10:1);

NMR(200 MHz, CDCl₃): δ7.93 (d, J=8.0 Hz, 1H), 7.40-6.96 (m, 8H), 3.80(q, J=7.4 Hz, 1H), 2.59 (t, J=7.8 Hz, 2H), 2.42-2.20 (m, 2H), 2.24 (t,J=6.8 Hz, 2H), 1.74-1.48 (m, 7H), 1.44-1.18 (m, 4H), 0.89 (t, J=6.6 Hz,3H).

EXAMPLE 2(2)4-[2-[2-[4-(2-phenylethoxy)phenyl]propanoylamino]phenyl]butanoic acid

TLC: Rf 0.28 (n-hexane:ethyl acetate=1:1);

NMR(300 MHz, CDCl₃): δ7.93 (d, J=8.4 Hz, 1H), 7.40-7.15 (m, 9H),7.10-7.00 (m, 2H), 6.95-6.85 (m, 2H), 4.16 (t, J=7.1 Hz, 2H), 3.77 (q,J=7.1 Hz, 1H), 3.09 (t, J=7.1 Hz, 2H), 2.33 (m, 2H), 2.25 (t, J=7.1 Hz,2H), 1.62 (m, 2H), 1.58 (d, J=7.1 Hz, 3H).

EXAMPLE 2(3)4-[4-cyano-2-[3-cyclopropyl-2-(1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.49 (chloroform:methanol=10:1);

NMR(300 MHz, CDCl₃): δ8.41 (s, 1H), 8.21 (d, J=7.5 Hz, 1H), 7.91 (m,1H), 7.84 (d, J=7.5 Hz, 1H), 7.69-7.46 (m, 5H), 7.28 (m, 1H), 7.09 (d,J=7.5 Hz, 1H), 4.61 (t, J=7.2 Hz, 1H), 2.32-1.96 (m, 6H), 1.36 (m, 2H),0.79 (m, 1H), 0.48-0.39 (m, 2H), 0.24-0.08 (m, 2H).

EXAMPLE 2(4)4-[2-[3-cyclopropyl-2-(1-naphthyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.53 (chloroform:methanol=10:1);

NMR(300 MHz, CDCl): δ8.22 (d, J 8.1 Hz, 1H), 7.93-7.80 (m, 3H), 7.67 (d,J=7.2 Hz, 1H), 7.59-7.47 (m, 3H), 7.18 (m, 1H), 7.00 (d, J 3.3 Hz, 2H),4.54 (t, J=7.2 Hz, 1H), 2.30-1.92 (m, 6H), 1.33 (m, 2H), 0.79 (m, 1H),0.48-0.36 (m, 2H), 0.26-0.08 (m, 2H),

EXAMPLE 2(5)4-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyl]butanoic acid

TLC: Rf 0.53 (chloroform:methanol=10:1);

NMR(300 MHz, CDCl₃): δ8.42 (s, 1H), 8.21 (d, J=8.1 Hz, 1H), 7.90 (m,1H), 7.84 (d, J=7.8 Hz, 1H), 7.66-7.48 (m, 5H), 7.28 (m, 1H), 7.09 (d,J=8.1 Hz, 1H), 4.60 (t, J=7.2 Hz, 1H), 2.34 (m, 1H), 2.20-1.88 (m, 5H),1.70 (m, 1H 1.34 (m, 2H), 1.24 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz,3H).

EXAMPLE 2(6) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.17 (n-hexane:ethyl acetate=1:1);

NMR(300 MHz, CDCl₃): δ8.36 (brs, 1H), 8.11 (brd, J=7.8 Hz, 1H), 7.92 (m,1H), 7.86 (brd, J=8.4 Hz, 1H), 7.62 (brd, J=6.3 Hz, 1H), 7.60-7.50 (m,3H), 7.33 (brs, 1H), 7.26 (dd, J=7.8, 1.8 Hz, 1H), 7.07 (d, J=7.8 Hz,1H), 4.60 (q, J=7.2 Hz, 1H), 2.03-1.87 (m, 4H), 1.82 (d, J=7.2 Hz, 3H),1.30-1.21 (m, 2H).

EXAMPLE 2(7) 4-[4-fluoro-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.55 (n-hexane:ethyl acetate=2:1);

NMR(300 MHz, CDCl₃): δ 8.12 (d, J=7.5 Hz, 1H), 7.93-7.85 (m, 3H), 7.62(d, J=6.3 Hz, 1H), 7.59-7.50 (m, 3H), 7.21 (br s, 1H), 6.90 (dd, J=8.4,6.3 Hz, 1H), 6.68 (dt, J=3.0, 8.4 Hz, 1H), 4.58 (q, J=7.2 Hz, 1H),1.94-1.82 (m, 7H), 1.23-1.13 (m, 2H).

EXAMPLE 2(8) 4-[4-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0,55 (n-hexane:ethyl acetate=2:1);

NMR(200 MHz, CDCl₃): δ8.14-8.04 (m, 2H), 7.94-7.84 (m, 2H), 7.64-7.49(m, 4H), 7.17 (br s, 1H), 6.97 (dd, J=8.0, 2.0 Hz, 1H), 6.89 (d, J=8.0Hz, 1H), 4.57 (q, J=7.2 Hz, 1H), 1.95-1.81 (m, 7H), 1.26-1.17 (m, 2H).

EXAMPLE 2(9) 4-[4-methyl-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.55 (n-hexane:ethyl acetate=2:1);

NMR(300 MHz, CDCl₃): δ8.14 (d, J=7.8 Hz, 1H), 7.92-7.84 (m, 2H),7.69-7.50 (m, 5H), 7.01 (br s, 1H), 6.87-6.80 (m, 2H), 4.55 (q, J=7.2Hz, 1H), 2.28 (s, 3H), 1.92-1.83 (m, 7H), 1.26-1.19 (m, 2H).

EXAMPLE 2(10)4-[4-cyano-2-[2-(4-methyl-1-naphthyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.45 (ethyl acetate),

NMR(300 MHz, CDCl₃): δ8.35 (s, 1H), 8.13-8.07 (m, 2H), 7.59-7.56 (m,2H), 7.50 (d, J=7.5 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.26(dd, J=7.8, 1.8 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 4.56 (q, J=7.2 Hz, 1H),2.72 (s, 3H), 1.99-1.90 (m, 4H), 1.81 (d, J=7.2 Hz, 3H), 1.29-1.19 (m,2H).

EXAMPLE 2(11)4-[4-cyano-2-[2-(1,2,3,4tetrahydro-5-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.64 (chloroform:methanol=9:1);

NMR(300 MHz, CDCl₃): δ 8.43 (brs, 1H), 7.35-7.02 (m, 6H), 4.04 (q, J=6.9Hz, 1H), 2.90-2.60 (m, 4H), 2.29-2.15 (m, 4H), 1.88-1.70 (m, 4H), 1.65(d, J=6.9 Hz, 3H), 1.56-1.44 (m, 2H).

EXAMPLE 2(12)4-[4-cyano-2-[2-(4-methoxy-1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.70 (chloroform:methanol=9:1);

NMR(300 MHz, CDCl₃): δ 8.39-8.34 (m, 2H), 8.01 (d, J=7.8 Hz, 1H),7.60-7.49 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.31 (brs, 1H), 7.25 (dd,J=8.1, 1.5 Hz, 1H), 7.05 (4, J=7.8 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.47(q, J 7.2 Hz, 1H), 4.03 (s, 3), 1.98-1.84 (m, 4H), 1.80 (d, J=7.2 Hz,3H), 1.30-1.18 (m, 2H).

EXAMPLE 2(13)4-[4-ethynyl-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.55 (n-hexane:ethyl acetate=1:2);

NMR(300 MHz, CDCl₃): δ8.13 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 7.93-7.84(m, 2H), 7.63-7.50 (m, 4H), 7.13 (dd, J=7.8, 1.5 Hz, 1H), 7.09 (s, 1H),6.93 (d, J=7.5 Hz, 1H), 4.57 (q, J=7.2 Hz, 1H), 3.01 (s, 1H), 1.94-1.89(m, 4H), 1.83 (d, J=7.2 Hz, 3H), 1.29-1.19 (m, 2H).

EXAMPLE 2(14)4-[4-cyano-2-[2-(benzothiophen-3-yl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.29 (n-hexane:ethyl acetate=1:2);

NMR(300 MHz, d₆-DMSO): δ12.10 (s, 1H), 9.74 (s, 1H), 8.01-7.95 (m, 2H),7.83 (d, J=1.8 Hz, 1H), 7.63 (s, 1H), 7.58 (dd, J=7.8, 1.8 Hz, 1H),7.46-7.34 (m, 3H), 4.35 (q, J=6.9 Hz, 1H), 2.59 (m, 2H), 2.08 (t, J=7.2Hz, 2H), 1.60 (m, 2H), 1.59 (d, J=6.9 Hz, 3H).

EXAMPLE 2(15)4-[4-cyano-2-[2-(4-fluoro-1-naphthyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.41 (chloroform:methanol=30:1);

NMR(300 MHz, CDCl₃): δ8.37 (brs, 1H), 8.20 (m, 1H), 8.12 (m, 1H);7.66-7.50 (m, 4H), 7.28 (dd, J 8.1, 1.8 Hz, 1H), 7.19 (dd, J=9.9, 8.1Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 4.57 (q, J=7.2 Hz, 1H), 2.20-2.00 (m,4H), 1.79 (d, J=7.2 Hz, 3H), 1.43-1.30 (m, 2H).

EXAMPLE 2(16)4-[4-cyano-2-[2(R)-(1-naphthyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.65 (ethyl acetate);

NMR(300 MHz, CDCl₃): δ8.37 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.94-7.85(m, 2H), 7.63-7.50 (m, 4H), 7.36 (s, 1H), 7.27 (dd, J=7.8, 1.8 Hz, 1H),7.07 (d, J=8.1 Hz, 1H), 4.60 (q, J=7.2 Hz, 1H), 2.04-1.92 (m, 4H), 1.82(d, J=7.2 Hz, 3H), 1.31-1.21 (m, 2H).

EXAMPLE 2(17) 4-[5-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:2);

NMR(300 MHz, DMSO): δ12.11 (s, 1H), 9.67 (s, 1H), 8.26 (d, J=8.7 Hz,1H), 7.95 (dd, J=7.2, 1.5 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.70-7.47 (m,7H), 4.77 (q, J=6.9 Hz, 1H), 2.56-2.54 (m, 2H), 2.07 (t, J=7.2 Hz, 2H),1.61-1.53 (m, 5H).

EXAMPLE 2(18)5-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]pentanoic acid

TLC: Rf 0.65 (ethyl acetate);

NMR(300 MHz, d₆-DMSO): δ11.95 (br s, 1H), 9.64 (s, 1H), 8.28 (d, J=8.1Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.85-7.80 (m, 2H), 7.62-7.48.(m, 5H),7.37 (d, J=8.1 Hz, 1H), 4.72 (q, J=6.9 Hz, 1H), 2.04-2.00 (m, 2H), 1.60(d, J=6.9 Hz, 3H), 1.27 (m, 4H).

EXAMPLE 2(19)3-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]propionic acid

TLC: Rf 0.45 (ethyl acetate);

NMR (300 MHz, d₆-DMSO): δ12.21 (br s, 1H), 9.82 (s, 1H), 8.26 (d, J=8.7Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.85-7.78 (m, 2H), 7.60-7.41 (m, 6H),4.73 (q, J=6.9 Hz, 1H), 2.80 (t, J=7.5 Hz, 2H), 2.41 (t, J=7.5 Hz, 2H),1.60 (d, J=6.9 Hz, 3H).

EXAMPLE 2(20)3-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyl]propionicacid

TLC: Rf 0.44 (chloroform:methanol=10:1);

NMR(300 MHz, CDCl₃): δ8.22-8.05 (m, 3H), 7.88 (m, 1H), 7.80 (d, J=8.4Hz, 1H), 7.66-7.44 (m, 4H), 7.29 (dd, J=7.8, 1.5 Hz, 1H), 7.11 (d, J=8.1Hz, 1H), 4.49 (t, J=7.2 Hz, 1H), 2.40-2.16 (m, 5H), 2.00 (m, 1H), 1.69(m, 1H), 1.02 (t, J=6.6 Hz, 3H), 0.98 (t, J=6.6 Hz, 3H).

EXAMPLE 2(21)4-[4-cyano-2-[2-(1,4-benzodioxan-5-yl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.59 (chloroform:methanol 9:1);

NMR(300 MHz, CDCl₃): δ8.38 (brs, 1H), 7.52 (brs, 1H), 7.33 (dd, J=7.8,1.5 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.97-6.83 (m, 3H), 4.40-4.25 (m,4H), 4.13 (q, J=7.2 Hz, 1H), 2.45-2.37 (m, 2H), 2.34-2.20 (m, 2H),1.72-1.61 (m, 2H), 1.58 (d, J=7.2 Hz, 3H).

EXAMPLE 2(22)4-[4-cyano-2-[2-(2-methyl-1-naphthyl)propanoylamino]phenyl]butanoic acid

TLC: Rf 0.60 (ethyl acetate);

NMR(300 MHz, CDCl₃): δ8.32 (s, 1H), 7.92-7.85 (m, 2H), 7.79 (d, J=8.4Hz, 1H), 7.51-7.39 (m, 3H), 7.26 (dd, J=7.8, 1.5 Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 6.98 (s, 1H), 4.59-4.57 (m, 1H), 2.62 (s, 3H), 1.89-1.70 (m,7H), 1.22-1.05 (m, 2H).

EXAMPLE 2(23)4-[4-cyano-2-[2-(2-methoxy-1-naphthyl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.70 (chloroform:methanol=9:1);

NMR(300 MHz, CDCl₃): δ8.36 (brs, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.90-7.83(m, 2H), 7.51 (m, 1H), 7.41-7.34 (m, 2H), 7.25 (dd, J=8.1, 1.5 Hz, 1H),7.13 (brs, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.84 (q, J=7.2 Hz, 1H), 3.99 (s,3H), 2.02-1.80 (m, 4H), 1.70 (d, J=7.2 Hz, 3H), 1.39-1.20 (m, 2H).

EXAMPLE 2(24) 4-[4cyano-2-[2-(indol-3-yl)propanoylamino]phenyl]butanoicacid

TLC: Rf 0.55 (ethyl acetate);

NMR(300 MHz, CDCl₃): δ8.44 (m, 2H), 7.70-7.64 (m, 2H), 7.42 (d, J=8.1Hz, 1H), 7.28-7.22 (m, 3H), 7.18-7.12 (m, 1H), 7.08 (d, J=7.8 Hz, 1H),4.14 (q, J=7.2 Hz, 1H), 2.06-1.95 (m, 4H), 1.76 (d, J=7.2 Hz, 3H),1.39-1.30 (m, 2H).

EXAMPLE 3 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanol

Under an atmosphere of argon, to a solution of the compound prepared inExample 2(6) (169 mg) in THF (1 ml), a solution of borane-THF complex(0.47 ml) was added at 0° C. The mixture was stirred for 5 hours at roomtemperature. Water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel to give the title compound (65mg) having the following physical data.

TLC: Rf 0.35 (n-hexane:ethyl acetate=1:2);

NMR(300 MHz, CDCl₃): δ8.38 (s, 1H), 8.10-8.07 (m, 1H), 7.95-7.88 (m,2H), 7.63-7.53 (m, 4H), 7.27-7.23 (m, 1H), 7.13 (s, 1H), 7.05 (d, J=8.1Hz, 1H), 4.54 (q, J=7.2 Hz, 1H), 3.35-3.25 (m, 2H), 1.90-1.85 (m,2H),1.84 (d, J=7.2 Hz, 3H), 1.06-0.90 (m, 4H),

EXAMPLE 4N-[4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoyl]-(3,5-dimethylisoxazol-4-yl)sulfonamide

To a solution of the compound prepared in Example 2 (150 mg) inmethylene chloride (2 ml), (3,5-dimethylisoxazol-4-yl)sulfonamide (147mg), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (120 mg) and4-dimethylaminopyridine (15 mg) were added. The mixture was stirredovernight at room temperature. 1M hydrochloric acid was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel, and washed with a mixture of methanol and water to give thetitle compound (121 mg) having the following physical data.

TLC: Rf 0.53 (n-hexane:ethyl acetate=2:3);

NMR(300 MHz, d₆-DMSO): δ12.3 (brs, 1H), 9.42 (brs, 1H), 8.28 (d, J=8.4Hz, 1H), 7.93 (m, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.60-7.45 (m, 4H), 7.25(m, 1H), 7.18-7.06 (m, 3H), 4.66 (q, J 6.9 Hz, 1H), 2.64 (s, 3H),2.40-2.30 (m, 2H), 2.36 (s, 3H), 2.11 (t, J=7.5 Hz, 2H), 1.58 (d, J=6.9Hz, 3H), 1.51 (m, 2H).

EXAMPLE 4(1)-4(2)

The following compounds were obtained by the same procedure as areaction of Example 4, using the compound prepared in Example 2(6) and acorresponding compound.

EXAMPLE 4(1)N-[4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoyl]benzenesulfonamide

TLC: Rf 0.53 (n-hexane:ethyl acetate=1:3);

NMR(300 MHz, d₆-DMSO): δ12.05 (s, 1H), 9.60 (s, 1H), 8.22 (d, J 8.4 Hz,1H), 7.95 7.88 (m, 3H), 7.82 7.75 (m, 2H), 7.70 (m, 1H), 7.65 7.41 (m,7H), 7.24 (d, J=8.4 Hz, 1H), 4.68 (q, J=6.9 Hz, 1H), 2.40 (m, 2H), 2.06(t, J=7.2 Hz, 2H), 1.56 (d, J=6.9 Hz, 3H), 1.45 (m, 2H).

EXAMPLE 4(2)N-[4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoyl]methanesulfonamide

TLC: Rf 0.33 (n-hexane:ethyl acetate=1:3);

NMR(300 MHz, d₆-DMSO) δ11.65 (br, 1H), 9.68 (s, 1H), 8.27 (d, J=8.1 Hz,1H), 7.95 (m, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H),7.6-7.47 (m, 5H), 7.38 (d, J=8.1 Hz, 1H), 4.74 (q, J=6.9 Hz, 1H), 3.21(s, 3H) 2.55 (m, 2H), 2.15 (t, J=7.2 Hz, 2H), 1.60 (m, 2H), 1.60 (d,J=6.9 Hz, 3H).

REFERENCE EXAMPLE 3 (2-nitrobenzyl)thioacetic acid

A solution of o-nitrobenzyl bromide (2.68 g) and potassium thioacetate(1.42 g) in acetone (20 ml) was refluxed for 2 hours. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate andconcentrated, and then (2-nitrobenzyl)thioacetate was obtained.

To a solution of the obtained compound and methyl bromoacetate (1.4 ml)in methanol (15 ml), sodium methoxide (737 mg) was added, and themixture was stirred for 1 hour at 45° C. Potassium t-butoxide (1.39 g)was added to the reaction mixture, and the mixture was stirred for 30minutes. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel to give the title compound (2.55 mg) havingthe following physical data.

TLC: Rf 0.26 (n-hexane:ethyl acetate=4:1);

NMR(200 MHz, CDCl₃): δ8.02 (dd, J=8.0, 1.0 Hz, 1H), 7.63-7.40 (m, 3H),4.21 (s, 2H), 3.72 (s, 3H), 3.09 (s, 2H).

EXAMPLE 5 2-[2-(1-naphthyl)propanoylamino]benzylthioacetic acid

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Reference example2→Example 1→Example 2, using the compound prepared in Reference example3.

TLC: Rf 0.34 (chloroform:methanol:water=90:10:1);

NMR(200 MHz, CDCl₃): δ8.12 (m, 1H), 7.96-7.78 (m, 3H), 7.72 (brs, 1H),7.66-7.46 (m, 4H), 7.26 (m, 1H), 7.04-6.96 (m, 2H), 4.53 (q, J=7.2 Hz,1H), 3.10 (d, J=13.6 Hz, 1H), 2.98 (d, J=13.6 Hz, 1H), 2.60 (s, 2H),1.86 (d, J=7.2 Hz, 3H).

EXAMPLE 5(1) 4-cyano-2-[2-(1-naphthyl)propanoylamino]benzylthioaceticacid

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Reference example3→Example 5, using a corresponding compound.

TLC: Rf 0.20 (ethyl acetate:methanol=9:1);

NMR(300 MHz, d₆-DMSO): δ9.74 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.97-7.94(m, 2H), 7.85 (d, J=7.8 Hz, 1H), 7.62-7.45 (m, 6H), 4.77 (q, J=6.9 Hz,1H), 3.90-3.79 (m, 2H), 3.05 (s, 2H), 1.61 (d, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 4N-(5-cyano-2-methoxymethoxyphenyl)-4methyl-2-(1-naphthyl)pentanamide

To a solution of 4-methyl-2-(1-naphthyl)valeryl chloride (490 mg) intoluene (4 ml), oxalyl chloride (190 μl) and dimethylformamide (DMF; onedrop) were added at room temperature. The mixture was stirred for 30minutes at 50° C. The reaction mixture was concentrated, and the residuewas dissolved into methylene chloride. The solution was dropped into asolution of 2-amino-4-cyano-1-methoxymethoxybenzene (480 mg) inmethylene chloride (5 ml), and then the mixture was stirred for 30minutes. 2N hydrochloric acid was added to the reaction mixture, and themixture was extracted with chloroform. The organic layer was washed witha saturated aqueous solution of sodium chloride, dried over magnesiumsulfate and concentrated The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=4:1) to give thetitle compound (684 mg) having the following physical data.

TLC: Rf 0.55 (n-hexane:ethyl acetate=2:1);

NMR(200 MHz, CDCl₃) δ8.71 (d, J=2.2 Hz, 1H), 8.20-8.08 (m, 1H),7.96-7.68 (m, 3H), 7.66-7.42 (m, 4H), 7.22 (dd, J=8.4, 1.8 Hz, 1H), 6.92(d, J=8.4 Hz, 1H), 4.82 (s, 2H), 4.48 (t, J=7.5 Hz, 1H), 2.98 (s, 3H),2.44-2.25 (m, 1H), 2.12-1.94 (m, 1H), 1.80 (m, 1H), 1.00 (d, J 6.8 Hz,3H), 0.97 (d, J 6.8 Hz, 3H).

REFERENCE EXAMPLE 5N-(5-cyano-2-hydroxyphenyl)-4-methyl-2-(1-naphthyl)pentanamide

To a solution of the compound prepared in Reference example 4 (684 mg)in dioxane (3 ml), 4N hydrochloric acid/dioxane (2.2 ml) was added at 0°C. The mixture was stirred for 5 hours at room temperature. The reactionmixture was concentrated and distilled off an azeotropic mixture withtoluene to give the title compound (593 mg) having the followingphysical data.

TLC: Rf 0.25 (n-hexane:ethyl acetate=2:1);

NMR (200 MHz, d₆-DMSO): δ11.13 (brs, 1H), 9.61 (s, 1H), 8.48-8.34 (m,2H), 8.00-7.78 (m, 2H), 7.70-7.32 (m, 5H), 6.95 (d, J=8.4 Hz, 1H),5.02-4.88 (m, 1H), 2.20-1.96 (m, 1H), 1.74-1.46 (m, 2H), 1.03 (d, J=6.0Hz, 3H), 0.91 (d, J=6.0 Hz, 3H).

EXAMPLE 6

4-cyano-2-[4methyl-2-(1-naphthyl)pentanoylamino]phenyloxyacetic acidethyl ester

To a solution of the compound prepared in Reference example 5 (290 mg)in acetone (4 ml), potassium carbonate (340 mg), ethyl bromoacetate(0.14 ml) and sodium iodide (12 mg) were added. The mixture was stirredfor 2 hours at 50° C. The reaction mixture was cooled to roomtemperature, and filtered. The filtrate was poured into water, and themixture was extracted with ether. The organic layer was a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate andconcentrated. The residue was putrified by column chromatography onsilica gel (n-hexan:ethyl acetate=1:1) to give the title compound (349mg) having the following physical data.

TLC: Rf 0.67 (n-hexane:ethyl acetate=1:1);

NMR(300 MHz, CDCl₃): δ8.76 (d, J=2.1 Hz, 1H), 8.24-8.06 (m, 2H),7.91-7.77 (m, 2H), 7.67-7.46 (m, 4H), 7.27-7.21 (m, 1H), 6.70 (d, J=8.1Hz, 1H), 4.52 (t, J=7.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.38-2.26 (m,1H) 2.02-1.90 (m, 1H), 1.76-1.60 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.02(d, J=6.6 Hz, 3H), 0.97 (t, J=6.6 Hz, 3H).

EXAMPLE 74-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyloxyacetic acid

The title compound (159 mg) having the following physical data wasobtained by the same procedure as a reaction of Example 2, using thecompound prepared in Example 6 (349 mg).

TLC: Rf 0.19 (chloroform:methanol=5:1);

NMR(200 MHz, CDCl₃): δ8.66 brs, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.00 (s,1H), 7.94-7.72 (m, 2H), 7.68-7.38 (m, 4H), 7.30-7.16 (m, 1H), 6.69 (d,J=8.8 Hz, 1H), 4.60-4.40 (m, 1H), 4.47 (s, 2H), 2.40-2.18 (m, 1H),2.10-1.86 (m, 1H), 1.78-1.50 (m, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.95 (d,J=7.0 Hz, 3H).

EXAMPLE 7(1) 4-cyano-2-[2-(1-naphthyl)propanoylamino]benzyloxyaceticacid

The title compound having the following physical data was obtained bythe same procedure as a reaction of Reference example 4→Referenceexample 5→Example 6→Example 7, using a corresponding compound.

TLC: Rf 0.10 (ethyl acetate:methanol=9:1);

NMR(300 MHz, CDCl₃): δ8.61 (s, 2H), 8.11-8.08 (m, 1H), 7.92-7.89 (m,1H), 7.83 (d, J=8.1 Hz, 1H), 7.59-7.47 (m, 4H), 7.30-7.27 (m, 1H), 7.14(d, J=8.1 Hz, 1H), 4.60 (q, J=7.2 Hz, 1H), 4.18 (d, J=11.1 Hz, 1H), 4.06(d, J=11.1 Hz, 1H), 3.55 (d, J=17.1 Hz, 1H), 3.48 (d, J=17.1 Hz, 1H),1.78 (d, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 64-t-butoxycarbonylamino-3-(4-methoxymethyloxy-2-butenyl)pyridine

To a solution of t-butyldicarbonate (9.59 g) in THF (40 ml),4-aminopyridine (3.76 g) was added. The mixture was stirred for 1 hourat room temperature. The solvent was distilled off from the reactionmixture. The obtained solid was washed with hexane/ethyl acetate (1:2),and the solid was obtained by filtration. To a solution of the obtainedsolid in THF (35 ml), 1.6M n-butyl lithium (9.6 ml) was added at −78°C., and then the mixture was stirred for 2 hours at 0° C. The mixturewas cooled −78° C., and a solution of 4-bromo-1-methoxymethoxy-2-butene(1.5 g) in THF (4.0 ml) was dropped into the mixture slowly. The mixturewas warmed until 10° C. under stirring for 2 hours. A saturated aqueoussolution of ammonium chloride was added to the mixture, and then themixture was extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of sodium chloride, driedover magnesium sulfate and concentrated. The residue was purified bycolumn chromatography on silica gel to give the title compound (394 mg)having the following physical data and 4-t-butoxycarbonylaminopyridine.

TLC: Rf 0.13 (n-hexane:ethyl acetate=1:1),

NMR(300 MHz, CDCl₃) δ8.37 (d, J=6.0 Hz, 1H), 8.30 (s, 1H), 8.02 (d,J=6.0 Hz, 1), 5.80 (m, 1H), 5.60 (m, 1H), 4.73 (s, 2H), 4.26 (d, J=6.3Hz, 2H), 3.47 (brd, J=7.5 Hz, 2H), 3.42 (s, 3H).

REFERENCE EXAMPLE 7N-t-butoxycarbonyl-N-[3-(4methoxymethyloxy-2-butenyl)pyridin-4-yl]-2-naphythylpropanamide

A solution of the compound prepared in Reference example 6 (384 mg) andoxalyl chloride (0.25 ml) in methylene chloride (6.4 ml), DMF (2 μl) wasdropped, and the mixture was stirred for 1 hour at room temperature. Thereaction mixture was concentrated. The residue was dissolved intodichloroethane (5.0 ml), and then the solution was stirred for 3 hoursat 50° C. The reaction mixture was poured into ice water, and extractedwith ethyl acetate. The organic layer was washed with 1N hydrochloricacid, water, a saturated aqueous solution of sodium bicarbonate, waterand a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel to give the title compound (290 mg) havingthe following physical data.

TLC: Rf 0.60 (n-hexane:ethyl acetate=1:1);

NMR(300 MHz, CDCl₃): δ8.48-8.43 (m, 10/5H), 8.37 (d, J=6.0 Hz, 3/5H),8.15 (m, 2/5H), 8.10-8.04 (m, 5/5H), 7.86 (m, 5/5H), 7.76 (m, 5/5H),7.58-7.37 (m, 20/5H), 6.83 (d, J=5.4 Hz, 2/5H), 6.75 (d, J=5.4 Hz,3/5H), 5.80-5.37 (m, 15/5H), 4.67 (s, 6/5H), 4.55 (s, 4/5H), 4.17 (brd,J=7.8 Hz, 6/5H), 3.93 (d, J=7.8 Hz, 4/5H), 3.40 (s, 9/5H), 3.33 (m,6/5H), 2.93 (brd, J=6.9 Hz, 4/5H), 1.68 (d, J=7.2 HZ, 1H), 1.61 d, J=7.2Hz, 1H), 1.21 (s, 18/5H), 1.07 (s, 27/5H).

REFERENCE EXAMPLE 8N-t-butoxycarbonyl-N-[3-(4-methoxymethyloxybutyl)pyridin-4-yl]-2-naphythylpropanamide

To a solution of the compound prepared in Reference example 7 (275 mg)in methanol (3.7 ml), 10% palladium carbon (27.5 mng) was added under anatmosphere of argon. The mixture was stirred for 4 hours at roomtemperature under an atmosphere of hydrogen gas. The reaction mixturewas replaced with argon and was filtered through celite (registeredtrademark), the filtrate was concentrated to give the title compound(276 mg) having the following physical data.

TLC: Rf 0.49 (n-hexane:ethyl acetate=1:1);

NMR(300 MHz, CDCl₃): δ8.49 (s, 1/2H), 8.45 (s, 1/2H), 8.42 (d, J=5.1 Hz,1/2H), 8.35 (d, J=5.1 Hz, 1/2H), 8.17-8.08 (m, 2/2H), 7.86 (brd, J=6.6Hz, 2/2H), 7.78 (brd, 8.1 Hz, 2/2H), 7.59-7.39 (m, 8/2M, 6.83 (d, J=5.4Hz, 1/2H), 6.75 (d, J=5.1 Hz, 1/2H), 5.84 (q, J=6.9 Hz, 1/2H), 5.78 (q,J=6.9 Hz, 1/2H), 4.61 (s, 2/2H), 4.51 (s, 2/2H), 3.52 (m, 2/2H), 3.36(s, 3/2H), 3.30 (s, 3/2H), 3.26 (t, J=6.0 Hz, 2/2H), 2.52-2.38 (m,2/2H), 2.14-2.02 (m, 2/2H), 1.73-1.57 (m, 8/2H), 1.23 (s, 9/2H), 1.06(s, 9/2H).

EXAMPLE 8 N-[3-(4-hydroxybutyl)pyridin-4yl]-2-naphythylpropanamide

To a solution of the compound prepared in Reference example 8 (267 mg)in methanol (2.0 ml), a solution of 4N hydrochloric acid and dioxane(5.0 ml) was added, and then the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated to give the titlecompound having the following physical data.

TLC: Rf 0.55 (chloroform:methanol=9:1);

NMR(300 MHz, CDCl₃): δ8.92 (d, J=6.6 Hz, 1H), 8.56 (dd, J=6.6 Hz, 1H),8.50 (brs, 1H), 8.22 (brd, J=8.1 Hz, 1H), 8.00 (m, 1H), 7.92 (brd, J=8.1Hz, 1H), 7.67-7.46 (m, 5H), 4.97 (q, J=7.2 Hz, 1H), 3.39-3.34 (m, 2H),2.65-2.46 (m, 2H), 1.78 (d, J=7.2 Hz, 3H), 1.32-1.11 (m, 4H).

EXAMPLE 9

4-[4-[2-(1-naphthyl)propanoylamino]pyridin-3-yl]butanoic acid

To a solution of the compound prepared in Example 8 indimethylsulfoxide/ethyl acetate (1:1, 4 ml), triethylamine (0.45 ml) andpyridine sulfonate (258 mg) were added under cooling with ice. Themixture was stirred for 2 hours. Water was added to the reactionmixture, and the mixture was washed with ethyl acetate. The solution wasneutralized by adding 1N hydrochloric acid and extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over magnesium sulfate, and concentrated toobtain the oil (188 mg). A solution of the oil (178 mg) and2-methyl-2-butene (0.5 ml) in t-butanol (10 ml), an aqueous solution(4.0ml) of sodium chlorite (93 mg) and sodium dihydrogenphosphate (96 mg)was added, and then the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated. Water was added tothe residue, and the mixture was extracted with chloroform. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over magnesium sulfate and concentrated to give the title compound(45 mg) having the following physical data.

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR (300 MHz, DMSO-d₆): δ9.62 (s, 1H), 8.33 (s, 1H), 8.32 (d, J=5.4 Hz,1H), 8.25 (d, J=8.7 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.8 Hz,1H), 7.77 (d, J=5.4 Hz, 1H), 7.62-7.47 (m, 4H), 4.85 (q, J=7.2 Hz, 1H),2.62=2.56 (m, 2H), 2.11 (dd, J=7.5, 6.9 Hz, 2H), 1.61 (d, J=7.2 Hz, 3H),1.58 (m, 1H), 1.12 (dt, J=23.7, 7.2 Hz, 1H).

REFERENCE EXAMPLE 9 N-methyl-2-nitrobenzylaminoacetic acid

To a solution of N-methylglycine methyl ester hydrochloride (2.00 g) inmethanol (20 ml), potassium hydroxide (300 mg) was added, and then themixture was stirred for 10 minutes at room temperature. To thesuspension, o-nitrobenzaldehyde (1.74 g) was added, and then the mixturewas stirred overnight at room temperature. A solution of sodiumcyanoborohydride (722 mg) in methanol was added to the reaction mixture,and the mixture was stirred for 4 hours at room temperature. A saturatedaqueous solution of sodium bicarbonate was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel to give the titlecompound (660 mg) having the following physical data.

TLC: Rf 0.24(n-hexane:ethyl acetate=4:1);

NMR(300 MHz, CDCl₃): δ7.84 (dd, J=8,1, 1.2 Hz, 1H), 7.68 (m, 1H), 7.56(m, 1H), 7.40 (m, 1H), 4.04 (s, 2H), 3.71 (s, 3H), 3.33 (s, 2H), 2.37(s, 3H).

EXAMPLE 10 N-methyl-2-[2-(1-naphthyl)propanoylamino]benzylanminoaceticacid hydrochloride

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Reference example2→Example 1→Example 2, using the compound prepared in Reference example9.

TLC: Rf 0.20 (chloroform:methanol=9:1);

NMR(300 MHz, d₆-DMSO): δ10.49 (br, 1H), 10.20 (brs, 1H), 8.33 (d, J=7.8Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65 7.36 (m,7H), 7.27 (m, 1H), 4.80 (q, J=6.9 Hz, 1H), 4.25 (br, 2H), 3.90 (br, 2H),2.55 (br, 3H), 1.61 (d, J=6.9 Hz, 3H).

EXAMPLE 10(1) 2-[2-(1-naphthyl)propanoylamino]benzylaminoacetic acidhydrochloride

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Reference example9→Example 10, using a corresponding compound.

TLC: Rf 0.21 (chloroform:methanol=4:1);

NMR(300 MHz, d₆-DMSO): δ10.13 (brs, 1H), 9.40 (br, 2H), 8.32 (d, J=8.1Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.65 7.48 (m,5H), 7.40 (m, 1H), 7.35 7.25 (m, 2H), 4.76 (q, J=7.2 Hz, 1H), 4.04 (brs,2H), 3.74 (brs, 2H), 1.62 (d, J=7.2 Hz, 3H).

EXAMPLE 11 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid (2-hydroxy)ethyl ester

To a solution of the compound prepared in Example 2(6) (150 mg) and2-iodoethanol (100 mg) in DMF (2 ml), potassium carbonate (65 mg) wasadded under an atmosphere of argon. The mixture was stirred forovernight at room temperature. Water was added to the reaction mixture,and then the mixture was extracted with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over and concentrated to give the crude crystal. Thecrude crystal was recrystallized with ethyl acetate/hexane to give thetitle compound (95 mg) having the following physical data.

EXAMPLE 11(1)-11(4)

The following compounds were obtained by the same procedure as areaction of Example 11, using the compound prepared in Example 2(6) anda corresponding compound instead of 2-iodoethanol.

EXAMPLE 11(1) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid diethylaminocarbonyl methyl ester

TLC: Rf 0.74 (ethyl acetate);

NMR(300 MHz, CDCl₃): δ8.40 (brs, 1H), 8.18 8.08 (m, 2H), 7.90 (m, 1H),7.82 (d, J=8.1 Hz, 1H), 7.62 (m, 1H), 7.56 7.47 (m, 3H), 7.27 (dd,J=7.8, 1.5 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.64 (q, J=7.2 Hz, 1H), 4.61(d, J=14.4 Hz, 1H), 4.33 (d, J=14.4 Hz, 1H), 3.32 (m, 2H), 3.16 (m, 2H),2.33 (m, 2H), 2.20 (t, J=6.6 Hz, 2H), 1.78 (d, J=7.2 Hz, 3H), 1.52 (m,2H), 1.17 (t, J=7.2 Hz 3H), 1.08 (t, J=7.2 Hz, 3H).

EXAMPLE 11(2) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid ethoxycarbonylmethyl ester

TLC: Rf 0.22 (n-hexane:ethyl acetate 3:1);

NMR(300 MHz, CDCl₃): δ8.45 (d, J=1.5 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H),7.91 (m, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65-7.49 (m, 5H), 7.27 (dd,J=8.1, 1.5 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.64 (q, J=7.2 Hz, 1H), 4.50(d, J=15.6 Hz, 1H), 4.44 (d, J=15.6 Hz, 1H), 4.20 (m, 2H), 2.15 (m, 4H),1.79 (d, J=7.2 Hz, 3H), 1.38 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).

EXAMPLE 11(3) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid dimethylainocarbonylmethyl ester

TLC: Rf 0.38 (n-hexane:ethyl acetate=1:3);

NMR(300 MHz, CDCl₃) δ8.42 (bs, 1H), 8.28 (bs, 1H), 8.09 (m, 1H), 7.91(m, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.64 7.47 (m, 4H), 7.28 (dd, J=8.1, 1.5Hz, 1H), 7.16 (d, J=8.1 Hz, 1H), 4.62 (q, J=6.9 Hz, 1H) 4.61 (d, J=15.0Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 2.83 (s, 3H), 2.81 (s, 3H), 2.41 (m,2H), 2.22 (m, 2H), 1.75 (d, J=6.9 Hz, 3H), 1.60 (m, 2H).

EXAMPLE 11(4) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid (2-methoxy)ethyl ester

TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1);

NMR(300 MHz, CDCl₃): δ8.50 (bs, 1H), 8.16 (m, 1H), 7.94 7.81 (m, 3H),7.62 (d, J=7.2 Hz, 1H), 7.58 7.48 (m, 3H), 7.27 (dd, J=7.8, 1.8 Hz, 1H),7.10 (d, J=7.8 Hz, 1H), 4.71 (q, J=7.2 Hz, 1H), 4.11 (ddd, J=12.3, 5.4,3.6 Hz, 1H), 3.98 (ddd, J=12.3, 5.4, 3.6 Hz, 1H), 3.50 (m, 2H), 3.38 (s;3H), 2.20 2.00 (m, 4H), 1.79 (d, J=7.2 Hz, 3H), 1.38 (m, 2H).

FORMULATION EXAMPLE 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 5 mg of active ingredient.

4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid . . . 500 mg

Carboxymethylcellulose calcium (disintegrating agent) . . . 200 mg

Magnesium stearate (lubricating agent) . . . 100 mg

Microcrystalline cellulose . . . 9.2 g

What is claimed:
 1. A carboxylic acid compound of formula (I)

wherein R¹ is COOH or COOR⁶, R⁶ is C1-6 alkyl, (C1-4 alkylene)—R¹⁶, R¹⁶is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR⁸R⁹, R⁸ and R⁹each independently is hydrogen or C1-4 alkyl, A is C2-6 alkylene, R² isC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF₃,cyano, nitro, hydroxy, NR¹¹R¹², CONR¹¹R¹², SO₂NR¹¹R¹²,or—S(O)_(x)—(C1-6)alkyl, m is 0, 1 or 2, when m is 2, then two R² may besame the or different, R¹¹ and R¹² each independently is hydrogen orC1-4 alkyl, x is 0, 1 or 2, B ring is phenyl, R³ is hydrogen or C1-4alkyl, R⁴ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4)C3-6 cycloalkyl, (5) hydroxy, (6) C1-4 alkoxy, (7) C1-4alkoxy(C1-4)alkoxy, or (8) C1-8 alkyl substituted by 1-2 of substituentsselected from halogen atom, hydroxy, C1-6 alkoxy, C1-4alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl, R⁵ is unsubstitutedphenyl or naphthyl or phenyl or naphthyl substituted by 1-2 of R¹³, R¹³is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF₃, cyano, C1-4alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, —(C1-4alkylene)_(y)—J—(C1-8 alkylene)_(z)—R¹⁴, benzoyl or thiophenecarbonyland two R¹³ may be the same or different, y is 0 or 1, z is 0 or 1, R¹⁴is phenyl or pyridyl, J is oxygen, S(O)_(t) or NR¹⁵, t is 0, 1 or 2, R¹⁵is hydrogen, C1-4 alkyl or acetyl; or non-toxic salts.
 2. A carboxylicacid compound of formula (I) according to the claim 1, wherein R¹ isCOOH or COOR⁶, R⁶ is C1-6 alkyl, (C1-4 alkylene)—R¹⁶, R¹⁶ is hydroxy,C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR⁸R⁹, R⁸ and R⁹ eachindependently is hydrogen or C1-4 alkyl, A is C2-4 alkylene, R² is C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF₃ orcyano, B ring is phenyl, m is 0 or 1, R³ is hydrogen or C1-4 alkyl, R⁴is C1-8 alkyl, C3-6 cycloalkyl or C1-8 alkyl substituted by 1-2 of C3-6cycloalkyl, R⁵ is unsubstituted phenyl or naphthyl or phenyl or naphthylsubstituted by 1-2 of R¹³, R¹³ is C1-6 alkyl, C1-6 alkoxy, halogen atom,CF₃, cyano or —(C1-4 alkylene)_(y)—J—(C1-8 alkylene)_(z)—R¹⁴, y is 0, Jis oxygen, z is 1, R¹⁴ is phenyl; or non-toxic salts thereof.
 3. Acarboxylic acid compound of formula (I) according to the claim 1selected from (1) 4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid methyl ester, (2)4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid methylester, (3) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid butyl ester, (4) 4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (5) 4-[2-[2-(4-pentylphenyl)propanoylamino]phenyl]butanoic acid,(6) 4-[2-[2-[4-(2-phenylethoxy)phenyl]propanoylamino]phenyl]butanoicacid, (7)4-[4-cyano-2-[3-cyclopropyl-2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (8)4-[2-[3-cyclopropyl-2-(1-naphthyl)propanoylamino]phenyl]butanoic acid,(9) 4-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyl]butanoicacid, (10) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (11) 4-[4-fluoro-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (12) 4-[4-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (13) 4-[4-methyl-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (14)4-[4-cyano-2-[2-(4-methyl-1-naphthyl)propanoylamino]phenyl]butanoicacid, (16)4-[4-cyano-2-[2-(4-methoxy-1-naphthyl)propanoylamino]phenyl]butanoicacid, (17) 4-[4-ethynyl-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (19)4-[4-cyano-2-[2-(4-fluoro-1-naphthyl)propanoylamino]phenyl]butanoicacid, (20) 4-[4-cyano-2-[2(R)-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (21) 4-[5-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoicacid, (22) 5-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]pentanoicacid, (23) 3-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]propionicacid, (24)3-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyl]propionicacid, (26)4-[4-cyano-2-[2-(2-methyl-1-naphthyl)propanoylamino]phenyl]butanoicacid, (27)4-[4-cyano-2-[2-(2-methoxy-1-naphthyl)propanoylamino]phenyl]butanoicacid, (29) 4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanol,(30)N-[4-[2-[2-(1-naphthyl)propanoylamino]phenyl]butanoyl]-(3,5-dimethylisoxazol-4-γl)sulfonamide,(33) 2-[2-(1-naphthyl)propanoylamino]benzylthioacetic acid, (35)4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyloxyacetic acidethyl ester, (36)4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyloxyacetic acid,(38) N-[3-(4-hydroxybutyl)pyridin-4-γl]-2-naphythylpropanamide, (39)4-[4-[2-(1-naphthyl)propanoylamino]pyridin-3-γl]butanoic acid, (42)4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid(2-hydroxy)ethyl ester, (43)4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic aciddiethylaminocarbonyl methyl ester, (44)4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acidethoxycarbonylmethyl ester, (45)4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic aciddimethylaminocarbonylmethyl ester, and (46)4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoic acid(2-methoxy)ethyl ester or non-toxic salts thereof.
 4. A pharmaceuticalcomposition having an activity of Prostaglandin E₂ receptor antagonist,which comprises a carboxylic acid comnound of formula (I) according tothe claim 1 or non-toxic salts thereof as active ingredients.
 5. Apharmaceutical composition according to claim 4, wherein ProstaglandinE₂ receptors are EP₃, EP₄, or EP₃ and EP₄.